PROJECT SUMMARY/ABSTRACT RESEARCH SUMMARY: The thienopyridine clopidogrel is one of the most commonly prescribed medications, and this oral antiplatelet agent reduces the risk of cardiovascular events in acute coronary syndrome (ACS) patients. However, the pharmacodynamic response to clopidogrel varies between individuals, leaving those patients with lesser degrees of platelet inhibition at increased risk of cardiovascular events. One potential source of this variability is the metabolism of clopidogrel, which is a pro-drug requiring biotransformation to become an active antiplatelet compound. Cytochrome P450 (CYP) enzymes play a role in the metabolism, and we have recently identified that carriers of particular genetic variants in CYP2C19 (~30% of the population) have lower active clopidogrel metabolite levels, diminished platelet inhibition, and higher rates of adverse cardiovascular events as compared with non-carriers. There are other key proteins involved in thienopyridine absorption and metabolism, including the intestinal efflux pump P-glycoprotein (encoded by MDR1) and carboxylesterases 1 and 2 (encoded by CES1 and CES2). It remains unknown whether genetic variants in MDR1, CES1, and CES2 impact the pharmacologic and clinical response to clopidogrel or to the newer, third-generation, thienopyridine prasugrel. This proposal outlines a scientific plan to: (1) determine the impact of polymorphisms in genes involved in thienopyridine metabolism on active drug metabolite levels and platelet inhibition in healthy subjects treated with clopidogrel and prasugrel;(2) evaluate the influence of these genetic factors on adverse cardiovascular outcomes in ACS patients treated with thienopyridines;and, (3) conduct a clinical trial to test whether genetic variants in CYP2C19 and those identified in Aims 1 and 2 can be overcome by higher than the currently recommended dose of clopidogrel or treatment with prasugrel. Ultimately, identifying polymorphisms that affect individual responses to thienopyridines should help physicians select the optimal dose and drug for each patient. CANDIDATE: Dr. Jessica Mega trained in Internal Medicine at Brigham and Women's Hospital (BWH) and Cardiology at Massachusetts General Hospital. Over the last two years, she has participated in a cardiovascular research training program (NHLBI T32 HL07575) conducting clinical investigations with the TIMI Study Group (part of BWH and Harvard Medical School) and has earned a Masters in Public Health concentrating in biostatistics and epidemiology. She has been using biomarker and genetic information to understand the pathobiology of ACS patients and to evaluate the variability in the response to pharmacotherapies. Additionally, she has been training in clinical trial design and implementation. Over time, Dr. Mega envisions combining her interests in genetics and ACS clinical trials to conduct clinical trials that investigate the use of genetic information to tailor the application of pharmacotherapies. The proposal sets out a training program to guide Dr. Mega from a mentored trainee to an independent physician-scientist. Understanding and merging genetics and clinical trials requires the development of an advanced set of research skills. The initial mentored period will include training with established mentors (Drs. Eugene Braunwald and Marc Sabatine with the TIMI Study Group) and a multi-disciplinary advisory committee of experts in genetics, pharmacology, platelet biology, and cardiovascular clinical trials. Dr. Mega will transition to scientific independence in year three of the award when she leads the clinical trial set out in Aim 3. ENVIRONMENT: The Cardiovascular Division at BWH offers exposure to a diverse range of faculty members engaged in basic and clinical research activities, and the institution is committed to encouraging collaborations. Moreover, its leadership is dedicated to protecting Dr. Mega's research time and fostering her development as an independent physician-scientist. Dr. Mega will also have access to resources at the Harvard School of Public Health, the Broad Institute, and Harvard University. Specifically, Dr. Mega will continue her research with the TIMI Study Group, which was founded by Dr. Eugene Braunwald and has conducted clinical trials in ACS for more than 25 years. The group consists of 12 physicians, including Dr. Marc Sabatine, who has extensive experience using biomarker and genetic information to evaluate ACS patients. The research group also includes project managers, research assistants, statisticians, and administrative assistants. The clinical trials conducted by the TIMI Study Group provide large cohorts with highly standardized collection of detailed clinical information, randomized assignment to key therapeutic interventions, and careful, long-term evaluations with central adjudication. Blood samples from these trials are available for DNA analysis for the studies outlined in Aims 1 and 2 of this proposal. The TIMI Study Group also offers the appropriate training environment to provide Dr. Mega with the skills needed to lead the multicenter clinical trial described in Aim 3. PUBLIC HEALTH RELEVANCE: NARRATIVE Patients with particular genetic variants may not optimally respond to the thienopyridine clopidogrel (a widely- used antiplatelet medication in individuals with coronary artery disease) and therefore face a higher risk of having a major cardiac event. Identifying these genetic variants that impact the response to thienopyridine therapy and determining ways to overcome them should help physicians select the right drug and dose for each patient with coronary artery disease.